Construction of complex memories via parallel distributed cortical–subcortical iterative integration
Authors: Neil McNaughton, Seralynne D. Vann
Journal: Trends in Neurosciences (2022)

Construction of complex memory engrams requires subcortex as well as cortex.Hippocampus and prefrontal cortex are connected via parallel 'Papez' circuits, with the mamillary area a key waystation.The parallel circuits have an onion-like nesting, with each circuit connecting a specific processing level of the areas involved.These circuits span from reflexive 'survival circuits', via the supramammillary nuclei, to slow and sophisticated, via the medial mammillary nucleus.Circuits involving cerebellar cortex have a similar organization to those involving neocortex.These parallel distributed circuits allow iterative processing to integrate information related to situation and motivation in the construction of complex distributed engrams and enable their inclusion in the perception–action cycle. The construction of complex engrams requires hippocampal–cortical interactions. These include both direct interactions and ones via often-overlooked subcortical loops. Here, we review the anatomical organization of a hierarchy of parallel 'Papez' loops through the hypothalamus that are homologous in mammals from rats to humans. These hypothalamic loops supplement direct hippocampal–cortical connections with iterative reprocessing paced by theta rhythmicity. We couple existing anatomy and lesion data with theory to propose that recirculation in these loops progressively enhances desired connections, while reducing interference from competing external goals and internal associations. This increases the signal-to-noise ratio in the distributed engrams (neocortical and cerebellar) necessary for complex learning and memory. The hypothalamic nodes provide key motivational input for engram enhancement during consolidation. The construction of complex engrams requires hippocampal–cortical interactions. These include both direct interactions and ones via often-overlooked subcortical loops. Here, we review the anatomical organization of a hierarchy of parallel 'Papez' loops through the hypothalamus that are homologous in mammals from rats to humans. These hypothalamic loops supplement direct hippocampal–cortical connections with iterative reprocessing paced by theta rhythmicity. We couple existing anatomy and lesion data with theory to propose that recirculation in these loops progressively enhances desired connections, while reducing interference from competing external goals and internal associations. This increases the signal-to-noise ratio in the distributed engrams (neocortical and cerebellar) necessary for complex learning and memory. The hypothalamic nodes provide key motivational input for engram enhancement during consolidation. Memory is phylogenetically old. Important aspects of human memory are ancient: they are present in simple invertebrate circuits [1.Kandel E.R. 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As noted above, SuM and MBs are physically adjacent, and we suggest that they are also computationally similar, but as key nodes in distinct loops that have more engaged subcortex and cortex, respectively (Figure 1). They provide subcortical motivational input into parallel circuits that support hippocampocortical long-loop interactions. Papez [13.Papez J.W. A proposed mechanism of emotion.Arch. Neurol. Psychiatr. 1937; 38: 725-743Crossref Google Scholar] initially put forward his eponymous hypothalamically mediated hippocampus–cortex–hippocampus circuit as the basis of emotion [22.Vann S.D. Nelson A.J. The mammillary bodies and memory: more than a hippocampal relay.Prog. Brain Res. 2015; 219: 163-185Crossref PubMed Scopus (68) Google Scholar]. However, to later researchers, the role of the hippocampus in amnesia (particularly obvious in Henry Mollaison [38.Ogden J. Corkin S. Memories of H.M.in: Abraham W.C. Memory Mechanisms: A tribute to G.V. Goddard. 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Importantly, in both humans and rodents, many aspects of memory remain intact, such as in simple item discrimination tasks and procedural tasks [45.Van der Werf Y.D. et al.Deficits of memory, executive functioning and attention following infarction in the thalamus; a study of 22 cases with localised lesions.Neuropsychologia. 2003; 41: 1330-1344Crossref PubMed Scopus (289) Google Scholar,46.Oudman E. et al.Procedural learning and memory rehabilitation in Korsakoff's syndrome - a review of the literature.Neuropsychol. Rev. 2015; 25: 134-148Crossref PubMed Scopus (27) Google Scholar]. Rather than affecting a particular type of memory [47.McNaughton N. Wickens J. 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Other low-level inputs (including from the ventral tegmental nucleus) provide sensory, motor, autonomic, and arousal-related information and control the frequency of hippocampal theta pattern activity. The theta pattern, per se, is important for neural plasticity [59.Albers C. et al.Theta-specific susceptibility in a model of adaptive synaptic plasticity.Front. Comput. Neurosci. 2013; 7: 170Crossref PubMed Scopus (8) Google Scholar] and spatial learning [60.McNaughton N. et al.Restoring theta-like rhythmicity in rats restores initial learning in the Morris water maze.Hippocampus. 2006; 16: 1102-1110Crossref PubMed Scopus (159) Google Scholar]. 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In the context of goal processing, neocortex (particularly the interaction of anterior and posterior neocortex) can maintain representations of the external world but, we argue, would need the ascending inputs from the base of the Papez circuit to add key 'contextual/emotional/internal' information. In particular, if episodic memory (and mental time travel) depends on the cell assemblies originally postulated by Hebb [65.Hebb D.O. The Organization of Behavior: A Neuropsychological Theory. Wiley-Interscience, 1949Google Scholar], spatial and temporal direction could be added by SuM/MB theta-rhythmic control during circuit processing. The need for internal direction inputs for event processing would explain the importance of simple vestibular input for 'memory'. Therefore, the ascending inputs to SuM would inject position/emotion information into the base of the Papez circuit, while also having more direct connections to higher levels, including the hippocampus. The original circuit envisioned by Papez [13.Papez J.W. A proposed mechanism of emotion.Arch. Neurol. Psychiatr. 1937; 38: 725-743Crossref Google Scholar], while capturing the essence of a key unidirectional loop around the various regions, does not give an accurate representation of the multiple parallel Papez-architecture closed loops that it encompasses (Box 1 and Figure 1) and which all have their lowest nodes in SuM/MB. The length and number of these closed loops likely explain the fact that the range of frequencies of the (usually synchronous) theta rhythmicity covers the round trip time from cortex to subcortex and back for these circuits [66.Miller R. Cortico-hippocampal interplay: self-organizing phase-locked loops for indexing memory.Psychobiology. 1989; 17: 115-128Crossref Scopus (51) Google Scholar,67.Miller R. Cortico-Hippocampal Interplay and the Representation of Contexts in the Brain. Springer-Verlag, 1991Crossref Google Scholar]. One of the shortest is SuM→hippocampus→MB→SuM, in which iteration has been clearly demonstrated and directional control of the rhythmicity shown to vary with its acceleration and deceleration [68.Ruan M. et al.Bi-directional theta modulation between the septo-hippocampal system and the mammillary area in free-moving rats.Front. Neural Circuits. 2017; 11: 62Crossref PubMed Scopus (11) Google Scholar]. Multiple loops also fit with suggestions that the hippocampus uses 'big loop' iteration ‡The circuits can be referred to as recurrent but, computationally, 'recursion' is a process different to iteration. for not only episodic memory, but also 'integration of information across experiences' ([69.Koster R. et al.Big-loop recurrence within the hippocampal system supports integration of information across episodes.Neuron. 2018; 99: 1342-1354Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar] p. 1342) and likely other forms of inferential processing.Box 1Connections of SuM and MBs: two hierarchies of iterative loopsCortex–subcortex connections are complicated, involving sets of hierarchically organized parallel closed loops. The higher functional levels of the hippocampus proper (area CA1 and the subiculum/SUB) send direct input only to evolutionarily old parts of the frontal lobe (i.e., prefrontal allocortex). By contrast, the Papez circuit allows CA3 to control more evolutionarily recent frontal isocortex [13.Papez J.W. A proposed mechanism of emotion.Arch. Neurol. Psychiatr. 1937; 38: 725-743Crossref Google Scholar] via the MBs→anterior thalamic nuclei (ATN) §Loops through, for example, nucleus reuniens ,are also important [139.Joyce M.K.P. et al.Pathways for memory, cognition and emotional context: hippocampal, subgenual area 25, and amygdalar axons show unique interactions in the primate thalamic reuniens nucleus.J. Neurosci. 2022; 42: 1068-1089Crossref PubMed Scopus (0) Google Scholar] but beyond the scope of this article.§Loops through, for example, nucleus reuniens ,are also important [139.Joyce M.K.P. et al.Pathways for memory, cognition and emotional context: hippocampal, subgenual area 25, and amygdalar axons show unique interactions in the primate thalamic reuniens nucleus.J. Neurosci. 2022; 42: 1068-1089Crossref PubMed Scopus (0) Google Scholar] but beyond the scope of this article.→frontal cortex path. This ATN projection also allows the MBs wide influence on temporal lobe memory systems [119.Squire L.R. Zola-Morgan S. The medial temporal lobe memory system.Science. 1991; 253: 1380-1386Crossref PubMed Google Scholar], including the entorhinal cortex, retrosplenial cortex (RSp), and SUB (completing the Papez circuit). The MBs are much more than a 'relay', instead integrating hippocampal outflow with independent mnemonic inputs from Gudden's tegmental nuclei in the midbrain.The nuclei of the MBs are connected by an onion-like series of nested loops to parallel levels of the hippocampal formation (see Figure 1 in the main text). 'The different levels are unlikely to exist simply so as to pass unaltered information on to one another; each must allow some particular transformation or integration of its inputs. We propose that the hippocampus is a system of logical gates which allows different types of information to progress to different points of the circuit and hence to produce (or in many cases not produce) outputs from different levels of the system subject to different conditions.' ([50.Gray J.A. McNaughton N. The Neuropsychology of Anxiety: An Enquiry into the Functions of the Septo-Hippocampal System.2nd edn. Oxford University Press, 2000Google Scholar], p. 221). Importantly, the intrahippocampal connections are all in the same single direction. Thus, the hippocampal formation is rectifying (forcing information to pass in only one direction in the loops), as are the connections from SuM to MBs.Important features of the hippocampal 'onion' are: (i) initial, partially processed, output is from area CA3, 'relayed' by the lateral septum, to SuM; and (ii) the main final, highly processed, output is from SUB/RSp direct to MBs. The similarity of the parallel loops suggests similar computational function, but the specific connections suggest that SuM mediates reflexive [77.LeDoux J.E. Emotion, memory and the brain.Sci. Am. 1994; 270: 50-59Crossref PubMed Google Scholar] and SUB/RSp mediate sophisticated processing. That is, SuM controls subcortical processing, using partially processed (CA3) information and with no neocortical efference copy. Fully processed information from SUB/RSp goes directly to the higher (goal-processing) areas of prefrontal cortex and anterior cingulate, with an efference copy (often via collaterals [70.Kinnavane L. et al.Collateral projections innervate the mammillary bodies and retrosplenial cortex: a new category of hippocampal cells.eNeuro. 2018; 5 (ENEURO.0383-17.2018)Crossref PubMed Scopus (19) Google Scholar] and with similar cell-firing fields [120.Kitanishi T. et al.Robust information routing by dorsal subiculum neurons.Sci. Adv. 2021; 7eabf1913Crossref PubMed Scopus (9) Google Scholar]) going directly to MBs as part of 'slow and sophisticated' processing.The Papez circuit is also onion-like. Lateral, med